TRR 219:  Mechanisms of Cardiovascular Complications in Chronic Kidney Disease

• Subject Area: Medicine ; Biology
• Term: since 2018
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 322900939

Cardiovascular disease (CVD) is a major cause of mortality worldwide and in particular in patients with chronic kidney disease (CKD). However, the underlying pathophysiological processes of increased cardiovascular risk in CKD have been largely unclear. Pioneering in this field, the Transregional Collaborative Research Centre SFB/TRR219 has devoted itself to analyzing the multi-factorial aspects of CKD-related CVD caused by alterations in (i) the circulation and (ii) the myocardium in experimental and clinical studies. In the 1st funding period, the SFB/TRR219 achieved its aims to (1) characterize mediators relevant to CKD and their effect on cardiovascular pathophysiological processes, thereby contributing to the mechanistic understanding of CKD-related CVD; (2) identify novel mediators relevant to CKD with a strong impact on CVD; and (3) initiate clinical translation. The results of the 1st funding period demonstrate that:(i) Alterations of mediators involved in cardiovascular calcification, inflammation, oxidative stress, fibrosis, thrombotic risk and neurohumoral activation highly contribute to cardiovascular vulnerability in CKD;(ii) Increased cardiovascular risk in CKD results from an interplay of factors and mechanisms that induce maladaptive preconditioning of the CV system, thereby “priming” for cardiovascular damage and dysfunction, rather than single mediators are causative for the genesis and progression of CKD-associated CVD. (iii) Many of these multifactorial cardiovascular hits can be attributed to uremia-induced modifications of important mediators in CKD, offering opportunities for clinical translation and finally novel treatment strategies.This leads to the concept of "Multifactorial Interactions in CKD-associated CVD", which will be studied in the 2nd funding period. We will focus (1) on CKD-induced “Post-Translational Modifications” (PTMs) of key proteins, as well as on other target molecules which we identified to have an impact on calcification, inflammation, oxidative stress, fibrosis and coagulation, thereby priming for increased CVD in CKD. Supported by our clinical and experimental findings in the 1st funding period, we will also further (2) unravel “Maladaptive Preconditioning” of mediators, cells and tissue in CKD towards a state of being increasingly harmful or less protective for the cardiovascular system, with (3) “Second CV Hits” having a higher impact on CVD in CKD.The overall aim is to clarify the mechanisms of cardiovascular complications in CKD, triggering research translation in novel relevant applications and technologies to the benefit of the CKD patient.

• DFG Programme: CRC/Transregios
• International Connection: Switzerland

Current projects

• C01 - Vitamin-K-abhängige Mechanismen der kardiovaskulären Verkalkung bei CKD (Project Heads Floege, Jürgen ;  Kaesler, Nadine ;  Kramann, Rafael )
• C02 - The role of post-translational modifications of sortilin receptors in CKD (Project Head Göttsch, Ph.D., Claudia )
• C03 - Die Rolle von Protein-Mineral-Komplexen in der Mineral-Homöostase (Project Head Jahnen-Dechent, Wilhelm )
• C04 - Characterization and validation of mediators affecting myocardial infarction and vascular calcification in CKD (Project Head Jankowski, Joachim )
• C05 - Dissecting mechanisms of vascular calcification in CKD using single cell genomics (Project Head Kramann, Rafael )
• C07 - CKD and coagulation: dysregulation of the alternative complement pathway (Project Head Schütt, Katharina )
• C08 - Role of hematopoietic reprogramming in cardiorenal diseases (Project Heads Fliser, Danilo ;  Speer, Ph.D., Thimoteus )
• C10 - Dickkopf-3 (DKK3) as a mediator of cardiorenal injury (Project Heads Fliser, Danilo ;  Schunk, Stefan J. )
• M01 - PDGFR-Signalisierung bei CVD in CKD (Project Heads Boor, Ph.D., Peter ;  Floege, Jürgen )
• M02 - Role of renal sympathetic nerve activation in CKD-associated cardiovascular disease and the development of malignant arrhythmias (Project Heads Böhm, Michael ;  Hohl, Mathias ;  Linz, Ph.D., Dominik )
• M03 - Modulatory effects of SGLT2 inhibition on cardiac metabolism in CKD patients (Project Heads Lehrke, Michael ;  Marx, Nikolaus Albert Helmut )
• M04 - Interplay between calcium signaling and oxidative stress in pathogenic immune cells during CKD and associated CVD (Project Heads Maack, Christoph ;  Niemeyer, Ph.D., Barbara Anne ;  Prates Roma, Ph.D., Leticia ;  Speer, Ph.D., Thimoteus )
• M05 - Enhanced thrombotic risk and myocardial dysfunction of the infarcted heart in CKD (Project Heads Marx, Nikolaus Albert Helmut ;  Noels, Ph.D., Heidi )
• M07 - Immune cell-lipid interaction, a mechanism of CKD-induced vascular complications (Project Heads Kahles, Florian ;  van der Vorst, Emiel )
• MGK - Integrated Research Training Group: Cardiovascular complications in CKD (Project Heads Göttsch, Ph.D., Claudia ;  Jankowski, Joachim ;  Niemeyer, Ph.D., Barbara Anne )
• S01 - Translational integration and evaluation of experimental concepts by evaluation of cohorts from clinical studies, international registries and center-based cohorts (Project Heads Böhm, Michael ;  Kindermann, Ingrid ;  Mahfoud, Felix ;  Wagenpfeil, Stefan )
• S02 - Central platform for standardization and development of animal models and histopathological analyses (Project Heads Boor, Ph.D., Peter ;  Hohl, Mathias )
• S03 - Mass spectrometry to identify, quantify and localize novel regulators of pathological processes underlying CKD-associated CVD (Project Heads Jankowski, Joachim ;  Jankowski, Vera )
• Z01 - Central administrative project (Project Head Jankowski, Joachim )

Completed projects

• C09 - Role of interleukin-1α in CKD-associated cardiovascular complications (Project Heads Niemeyer, Ph.D., Barbara Anne ;  Speer, Ph.D., Thimoteus ;  Zewinger, Stephen )
• M06 - Effects of genetic Raf kinase inhibitor protein (RKIP), RAAS and eNOS modulation on adverse cardiovascular remodeling and senescence in CKD (Project Head Werner, Christian )

• Applicant Institution: Rheinisch-Westfälische Technische Hochschule Aachen
• Co-Applicant Institution: Universität des Saarlandes
• Spokesperson: Professor Dr. Joachim Jankowski